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Giant cell stromal reaction in squamous cell carcinomata

Electronmicroscopic and ultrahistochemical observations on the genesis and functional activity of multinucleated giant cells in bleomycin-induced tumor regression

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Summary

Ten cases of oral squamous cell carcinoma, treated by bleomycin, were studied by electron microscopy with particular regard to the stromal reaction. The genesis and phagocytic function of multinucleated giant cells of foreign body type were observed. These cells phagocytize devitalized, keratinized tumor cells in particular. Their genesis from monocytic macrophages and endocytosis of large keratinized tumor cells are described in detail. Both phenomena are connected and the mode of formation of the cells results in functional specialization. The initial stages of intracellular digestion do not seem to take place within membrane limited vacuoles but in specialized cytoplasmatic areas which are formed around the ingested material. These contain high concentrations of hydrolases, sealed off from the rest of the cell by a clear zone of organell-free cytoplasm. This unique form of phagocytosis and digestion (“gigantophagocytosis”) is only possible in these highly specialized giant cells and explains their biological significance. It is likely that secondary lysosomes are formed in subsequent stages of digestion.

The differences between our results and the experimental observations of other authors are discussed.

Zusammenfassung

10 FÄlle von Bleomycin-behandelten oralen Plattenepithelcarcinomen wurden hinsichtlich der Stromareaktion elektronenmikroskopisch untersucht. Hierbei wurde besonders die Genese und phagocytÄre Funktion von mehrkernigen Riesenzellen (vom Fremdkörpertyp) beobachtet. Diese phagocytieren vor allem devitalisierte, keratinisierte Tumorzellen. Die Genese aus monocytogenen Makrophagen und die Endocytose der gro\en Keratinlamellen werden detailliert beschrieben. Beide PhÄnomene sind untrennbar miteinander verknüpft (funktionelle Genese) und führen zu einer funktionellen Spezialisierung. Die Initialstadien der intracellulÄren Digestion finden nicht in membranbegrenzten Vakuolen statt, sondern in spezialisierten Cytoplasmaarealen. Diese enthalten hohe Konzentrationen an Hydrolasen und werden durch eine organellenfreie Zone von der übrigen Zelle abgeschirmt. Diese einzigartige Form der Phagocytose und Digestion („Gigantophagocytose”) ist nur in den hochspezialisierten Riesenzellen möglich und erklÄrt ihre biologische Bedeutung. Erst in den folgenden Schritten der Digestion kommt es zur Bildung von sekundÄren Lysosomen. Diese Riesenzellen besitzen eine hohe funktioneile AktivitÄt und Spezialisierung. Der Widerspruch dieser Beobachtung zu den experimentellen Befunden anderer Autoren wird diskutiert.

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References

  • Adams, D.O.: The structure of mononuclear phagocytes differentiating in vivo. 1. Sequential fine and histologic studies of the effect of Bacillus Calmette-Guerin (BCG). Amer. J. Path. 76, 17–48 (1974)

    Google Scholar 

  • Adams, D.O.: The granulomatous inflammatory response. A review. Amer. J. Path. 84, 164–185 (1976)

    Google Scholar 

  • Bassermann, F.J.: Untersuchungen an isolierten, lebenden oder lebend-fixierten tuberkulösen menschlichen Riesenzellen vom Langhans-Typ. Beitr. klin. Tuberk. 123, 294–311 (1961)

    Google Scholar 

  • Berdal, P., Iversen, O.H., Weyde, R.: Simultaneous intermittent bleomycin and radiological treatment of laryngeal cancer. Canad. J. Otolaryngol. 4, 219–224 (1975)

    Google Scholar 

  • Black, M.M., Epstein, W.L.: Formation of multinucleated giant cells in organized epitheloid cell granulomas. Amer. J. Path. 74, 263–274 (1974)

    Google Scholar 

  • Black, M.M., Fukuyama, K., Epstein, W.L.: The induction of human multinucleated monocytes in culture. J. Invest. Derm. 66, 90–92 (1976)

    Google Scholar 

  • Bönicke, R., Fasske, E., Themann, H.: Submikroskopische und enzymhistochemische BeitrÄge zur formalen Genese des Epitheloidzellgranuloms. Klin. Wschr. 41, 753–768 (1963)

    Google Scholar 

  • Breathnach, A.O.: Aspects of epidermal ultrastructure. J. Invest. Derm. 65, 2–15 (1975)

    Google Scholar 

  • Broders, A.C.: Squamous-cell epithelioma of the lip. A study of 537 cases. J. Amer. Med. Ass. 74, 656–664 (1920)

    Google Scholar 

  • Burkhardt, A., Hötje, W.-J.: The effects of intra-arterial bleomycin therapy on squamous cell carcinoma of the oral cavity. Biopsy and autopsy examinations. J. max.-fac. Surg. 3, 217–230 (1975)

    Google Scholar 

  • Burkhardt, A., Bommer, G., Gebbers, J.-O., Höltje, W.-J.: Riesenzellbildung bei Bleomycintherapie oraler Plattenepithelcarcinome. Enzymhistochemische, elektronenmikroskopische und ultrahistochemische Untersuchungen. Virchows Arch. Abt. A Path. Anat. and Histol. 369, 197–214 (1976a)

    Google Scholar 

  • Burkhardt, A., Höltje, W.-J., Gebbers, J.-O.: Vascular lesions following perfusion with bleomycin. Electron-microscopic observations. Virchows Arch. A Path. Anat. and Histol. 372, 227–236 (1976 b)

    Google Scholar 

  • Carter, R.L., Birbeck, M.S.C., Roberts, J.D.B.: Development of injection site sarcomata in rats: a study of the early reactive changes evoked by a carcinogenic nitrosoquinoline compound. Brit. J. Cancer 24, 300–311 (1970)

    Google Scholar 

  • Carter, R.L., Roberts, J.D.B.: Macrophages and multinucleate giant cells in nitrosoquinolineinduced granulomata in rats: an autoradiographic study. J. Path. 105, 285–288 (1971)

    Google Scholar 

  • Cohn, Z.A., Benson, B.: The differentiation of mononuclear phagocytes: morphology, cytochemistry and biochemistry. J. Exp. Med. 121, 153–170 (1965)

    Google Scholar 

  • Daems, W.Th., Wisse, E., Brederoo, P.: Electron microscopy of the vacuolar apparatus. In: Lysosomes in biology and pathology, Dingle, J.T. and Fells, H.B., eds., pp. 64–112. Amsterdam, London: North-Holland 1969

    Google Scholar 

  • Davis, J.M.G.: The ultrastructural changes that occur during transformation of lung macrophages to giant cells and fibroblasts in experimental asbestosis. Brit. J. Exp. Path. 44, 568–575 (1963)

    Google Scholar 

  • Dingle, J.T.: Vacuoles, vesicles, and lysosomes. Brit. Med. Bull. 24, 141–145 (1968)

    Google Scholar 

  • Evans, R.: Macrophages and the tumour bearing host. Brit. J. Cancer 28, Suppl. 1, 19–25 (1973)

    Google Scholar 

  • Gedigk, P., Bontke, E.: über die EnzymaktivitÄt im Fremdkörpergranulationsgewebe. Virchows Arch. A Path. Anat. 330, 538–568 (1957)

    Google Scholar 

  • Gillman, T., Wright, L.J.: Probable in vivo origin of multinucleated giant cells from circulating mononuclears. Nature 209, 263–265 (1966)

    Google Scholar 

  • Gössner, W.: Histoenzymatische Untersuchungen zur Tuberkulose. Verh., Dtsch. Ges. Path. 39, 152–157 (1956)

    Google Scholar 

  • Gusek, W.: Histologie und elektronenmikroskopische komparative Zytologie tuberkulöser und epitheloidzelliger Granuloma. Adv. Tuberc. Res. 14, 97–156 (1955)

    Google Scholar 

  • Gusek, W.: Die Feinstruktur der einkernigen Makrophagen und der mehrkernigen Riesenzellen im Fremdkörpergranulationsgewebe. Frankf. Z. Path. 69, 429–436 (1958)

    Google Scholar 

  • Gusek, W.: Histologische und vergleichende elektronenmikroskopische Untersuchungsergebnisse zur Zytologie, Histogenese und Struktur des tuberkulösen und tuberkuloiden Granuloms. Med. Welt 1964, 850–866

  • Hamperl, H.: Geschwulststroma. In: Handb. allg. Path., F. Büchner, E. Letterer. F. Roulet (Hrsg.), Bd. VI/3, S. 56–59. Berlin-Göttingen-Heidelberg: Springer 1956

    Google Scholar 

  • Haythorn, S.R.: Multinucleated giant cells. Arch. Path. 7, 651–713 (1929)

    Google Scholar 

  • Henson, P.: Interaction of cells with immune complexes: adherence, release of constituents, and tissue injury. J. Exp. Med. 134, 114S-135S (1971)

    Google Scholar 

  • Hodel, C.: Fermenthistochemische Befunde an Riesenzellen in Talkumgranulomen der Ratte. Path. Microbiol. 30, 27–34 (1967)

    Google Scholar 

  • Höltje, W.-J., Burkhardt, A., Gebbers, J.-O., Maerker, R.: Intraarterielle Bleomycintherapie von Plattenepithelcarcinomen der Mundhöhle. Klinik und pathologische Anatomie. Z. Krebsforsch. 88, 69–90 (1976)

    Google Scholar 

  • Holtrop, M.E., Raisz, L.G., Simmons, H.A.: The effects of parathyroid hormone, colchicine, and calcitonin on the ultrastructure and the activity of osteoclasts in organ culture. J. Cell Biol. 60, 346–355 (1974)

    Google Scholar 

  • Hornová, J., Bilder, J.: Histology of orofacial tumors perfused with bleomycin. Neoplasma 21, 599–605 (1974)

    Google Scholar 

  • Iversen, O.H.: Histological changes provoked by bleomycin. In: Bleomycin in the treatment of malignant diseases L. Christensen, Ed. Dorking, Surrey: Adlard & Son, Bartholomew Press 1974

    Google Scholar 

  • Kligman, A.M.: Biology of the stratum corneum. In: The epidermis, W. Montagna, W.C. Lobitz, Eds. New York: Academic Press 1964

    Google Scholar 

  • Komiyama, A., Spicer, S.S.: Ultrastructural localization of a characteristic acid phosphatase in granules of rabbit basophils. J. Histochem. Cytochem. 22, 1092–1104 (1974)

    Google Scholar 

  • Konjetzny, G.E.: Spontanheilung beim Karzinom, insbesondere beim Magencarcinom. Münch. Med. Wschr. 65, 292 (1918)

    Google Scholar 

  • Lambert, R.A.: The production of foreign body giant cells in vitro. J. Exp. Med. 15, 510–515 (1912)

    Google Scholar 

  • Langer, K.H.: Lysosomen und Heterophagie. Verh. Dtsch. Ges. Path. 60, 9–27 (1976)

    Google Scholar 

  • Leder, L.D., Nicolas, R.: Untersuchungen zur Genese der Fremdkörperriesenzellen mittels der Hautfenstermethode. Frankf. Z. Path. 74, 620–639 (1965)

    Google Scholar 

  • Lewis, W.H.: The formation of giant cells in tissue cultures and their similarity to those in tuberculous lesions. Amer. Rev. Tuberc. 15, 616–628 (1927)

    Google Scholar 

  • Luft, J.H.: Ruthenium red and violet. I. Chemistry, purification, methods of use for electron microscopy and mechanism of action. Anat. Rec. 171, 347–368 (1971 a)

    Google Scholar 

  • Luft, J.H.: Ruthenium red and violet. II. Fine structural localization in animal tissues. Anat. Rec. 171, 369–416 (1971 b)

    Google Scholar 

  • Mariano, M., Spector, W.G.: The formation and properties of macrophage polykaryons (inflammatory giant cells). J. Path. 113, 1–19 (1974)

    Google Scholar 

  • Mariano, M., Nikitin, T., Maincelli, B.E.: Immunological and non-immunological phagocytosis by inflammatory macrophages, epitheloid cells and macrophage polykaryons from foreign body granulomata. J. Path. 120, 151–159 (1976)

    Google Scholar 

  • Matoltsy, A.G.: The substructure and chemical nature of the horny cell membrane. J. Invest. Derm. 62, 343 (1974)

    Google Scholar 

  • Matoltsy, A.G., Balsamo, C.A.: A study of the components of the cornified epithelium of human skin. J. Biophys. Biochem. Cytol. 1, 339–360 (1955)

    Google Scholar 

  • Matoltsy, A.G., Parakkal, P.F.: Membrane-coating granules of keratinizing epithelia. J. Cell Biol. 24, 297–307 (1965)

    Google Scholar 

  • Nicolaides, N.: Lipids, membranes, and the human epidermis. In: The epidermis, W. Montagna and W.C. Lobitz, Eds., p. 511–538. New York, London: Academic Press 1964

    Google Scholar 

  • Orth, J.: über HeilungsvorgÄnge an Epitheliomen nebst allgemeinen Bemerkungen über Epitheliome. Z. Krebsforsch. 1, 399–412 (1904)

    Google Scholar 

  • Otto, H.F.: Elektronenmikroskopische Beobachtungen über Myelinfiguren bei chronischer Gastritis. Beitr. path. Anat. 140, 407–418 (1970)

    Google Scholar 

  • Papadimitriou, J.M.: Detection of macrophage receptors for heterologous IgG by scanning and transmission electron microscopy. J. Path. 110, 213–220 (1973)

    Google Scholar 

  • Papadimitriou, J.M., Finlay-Jones, J.M., Walters, M.N. I.: Surface characteristics of macrophages, epithelioid and giant cells using scanning electron microscopy. Exp. Cell Res. 76, 353–362 (1973 a)

    Google Scholar 

  • Papadimitriou, J.M., Sforsina, D., Papaelias, L.: Kinetics of multinucleate giant cell formation and their modification by various agents in foreign body reactions. Amer. J. Path. 73, 349–364 (1973 b)

    Google Scholar 

  • Papadimitriou, J.M., Archer, M.: The morphology of murine foreign body multinucleate giant cells. J. Ultrastruct. Res. 49, 372–386 (1974)

    Google Scholar 

  • Papadimitriou, J.M., Wyche, P.A.: An examination of murine foreign body giant cells using cytochemical techniques and thin layer chromatography. J. Path. 114, 75–83 (1974)

    Google Scholar 

  • Papadimitriou, J.M., Robertson, T.A., Walters, M.N.I.: An analysis of the phagocytic potential of multinucleated foreign body giant cells. Amer. J. Path. 78, 343–358 (1975)

    Google Scholar 

  • Papadimitriou, J.M., Wee, S.H.: Selective release of lysosomal enzymes from cell populations containing multinucleate giant cells. J. Path. 120, 193–199 (1976)

    Google Scholar 

  • Parakkal, P., Pinto, J., Hanifin, J.M.: Surface morphology of human mononuclear phagocytes during maturation and phagocytosis. J. Ultrastruct. Res. 48, 216–226 (1974)

    Google Scholar 

  • Pearse, A.G.E.: Histochemistry, theoretical and applied, 3rd ed., London: Churchill 1968

    Google Scholar 

  • Petersen, W.: BeitrÄge zur Lehre vom Carcinom. Bruns' Beitr. 32, 543–654 (1901)

    Google Scholar 

  • Poste, G., Allison, A.C.: Membrane fusion reaction: a theory. J. Theor. Biol. 32, 165–184 (1971)

    Google Scholar 

  • Queisser, W., Sandritter, W., Lennert, K.: Cytophotometrische Untersuchungen an Histiocyten, Epitheloidzellen und Langhansschen Riesenzellen bei Sarkoidose des Lymphknotens. Virchows Arch. B Zellpath. 1, 49–61 (1968)

    Google Scholar 

  • Ratzenhofer, M.: Ungewöhnliche Stromareaktion bei nicht behandelten Karzinomen. Zbl. Allg. Path. 113, 252–253 (1970 a)

    Google Scholar 

  • Ratzenhofer, M.: Klassifizierung der Stromareaktion bei Karzinom. Zbornik Radova I Kongresa Patologa Jugoslawije, Zagreb 13–15 X 1969. Radovi Medicinskog Fakulteta u Zagrebu. Acta Facultatis medicae Zagrebiensis, Vol. XVIII, Suppl. 1, S. 289–299 (1970)

    Google Scholar 

  • Renault, P., André, P., Laccourreye, H.: Cancers pharyngo-laryngés traités par la bléomycin. Essai de contrÔle histo-pathologique. Ann. Oto-laryng. (Paris) 89, 229–238 (1972)

    Google Scholar 

  • Ribbert, H.: HeilungsvorgÄnge im Carcinom nebst Anregung zu seiner Behandlung. Dtsch. Med. Wschr. 10, 278–281 (1916)

    Google Scholar 

  • Rowden, G.: Membrane-coating granules of mouse oesophageal and gastric epithelium. J. Invest. Derm. 47, 359–362 (1966)

    Google Scholar 

  • Sapp, J.P.: An ultrastructural study of nuclear and centriolar configurations in multinucleated giant cells. Lab. Invest. 34, 109–114 (1976)

    Google Scholar 

  • Schenk, R.K.: Ultrastruktur des Knochens. Verh. Dtsch. Ges. Path. 58, 72–83 (1974)

    Google Scholar 

  • Schulz, A.: Institut für Pathologie der UniversitÄt Hamburg; personal communication 1977

  • Sirtori, C., Pizzetti, F.: Regressioni spontanee di nidi metastatici linfoghiandolari da carcinomi spinocellulari (interpretazione e referimenti radiobiologici). Tumori 23, 130–136 (1949)

    Google Scholar 

  • Sutton, J.S., Weiss, L.: Transformation of monocytes in tissue culture into macrophages, epitheloid cells and multinucleated giant cells. J. Cell Biol. 28, 393–332 (1966)

    Google Scholar 

  • Sutton, J.S.: Ultrastructural aspects of in vitro development of monocytes into macrophages, epitheloid cells and multinucleated giant cells. Natl. Cancer Inst. Monogr. 26, 71–141 (1967)

    Google Scholar 

  • Wanstrup, J., Christensen, H.E.: Sarcoidosis. I. Ultrastructural investigations on epithelioid cell granulomas. Acta Pathol. Microbiol. Scand. 66, 169–185 (1966)

    Google Scholar 

  • Warfel, A.H., Elberg, S.S.: Macrophage membranes viewed through a scanning electron microscope. Science 170, 446–447 (1970)

    Google Scholar 

  • Wurm, E.: über die Entstehung der Fremdkörperriesenzellen. Beitr. path. Anat. 116, 149–167 (1956)

    Google Scholar 

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  1. Institut für Pathologie der UniversitÄt Hamburg, Martinistr. 52 (UKE), D-2000, Hamburg 20, Germany

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Supported in part by a grant from the „Deutsche Forschungsgemeinschaft”

The authors wish to express their sincere appreciation to Miss C. Schürmann for invaluable technical assistance in this project and to Dr. Dr. W.-J. Höltje, Nordwestdeutsche Kieferklinik, for providing the biopsy specimens and clinical data.

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Burkhardt, A., Gebbers, J.O. Giant cell stromal reaction in squamous cell carcinomata. Virchows Arch. A Path. Anat. and Histol. 375, 263–280 (1977). https://doi.org/10.1007/BF00427058

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